We reported the identification of highly conserved homologous regions located in the carboxy terminous of the HIV 1 gp41 (env) (aa 837-844), and the aminoterminal (aa 19-25) of all human HLA class II beta chains. Murine monoclonal antibodies, raised against the gp41 derived synthetic peptide, bound to both gp41 and HLA class II derived peptides, as well as to "native" HLA class II molecules. These mAb could block activation of normal human CD4+ lines. The possibility that HIV-1 infection may lead to the generation of such cross-reactive antibodies was tested by screening sera from many HIV-1 patients as well as relevant controls. It was found that 30-40% of sera from patients at all stages of the disease, contained such anti-class II CRAb. It was also demonstrated that the sera containing these CRAb cells to recall antigens such as tetanus toxoid and to allogeneic stimulation.These sera could also mediate antibody dependent cellular cytotoxicity (ADCC) of class II-bearing cell lines. Both reactivities could be absorbed by and eluted from class II-peptide-linked sepharose column, and were found to be mediated by IgG antibodies.The possible contribution of these CRAb to the establishment of the immunodeficiency state and/or disease progression in HIV-1 infected individuals was examined in two clinical studies: I. Asymptomatic patients (WR 1-2, CD4 cells >500/mm3), were tested in parallel for their T cell responses to recall antigens (tetanus toxoid/flu), PHA, and allostimulation. It found that about 50% of these early patients lost their responses to recall antigens. The same patients were found to have high titers of anti-class II CRAb (p<.001). II. Retrospective study of HIV-1 infected hemophiliacs, suggested that patients with high titers of CRAb early in the disease, progressed faster to full blown AIDS. We continue these studies and also screen sera from different vaccine groups for the presence of such unwanted antibodies.